恩其明醋酸盐的药代动力学研究

目的：研究恩其明醋酸盐（ＡＴ１８４０）在大鼠体内的药代动力学。方法：荧光检测法。结果：大鼠静注后，其体内的血药浓度－时间曲线符合二室开放模型。其分布相Ｔ１２α为０．５７ｍｉｎ，消除相Ｔ１２β为５．５１ｍｉｎ。大鼠ｉｖＡＴ１８４０后，组织中的药物浓度，以肺、肾浓度最高，肝、卵巢、心、脾、胃次之，肌肉、脂肪、脑中最低。尿中排泄量２４ｈ内占总给药量的２３．２８％；胆汁和粪中分别约为给药量的３６．４６％和１．７９％。ＡＴ１８４０与血浆蛋白的结合率６８．５％～７３．９％。结论：ＡＴ１８４０是一个血浆半衰期短，并有组织分布选择性的药物。     

蛇毒神经生长因子在大鼠体内的药物代谢动力学与周围神经分布

用［１２５Ｉ］标记结合高效液相色谱法和酸沉法研究大鼠体内蛇毒神经生长因子（ｖＮＧＦ）药物代谢动力学．［１２５Ｉ］ｖＮＧＦ体外有刺激神经突起生长活性．药后血清存在游离和结合［１２５Ｉ］ｖＮＧＦ及［１２５Ｉ］降解物．１２ｍｇ·ｋｇ－１ｉｖ后ｔ１／２α为０．１３ｈ，ｔ１／２β为３．８ｈ；１２和４８ｍｇ·ｋｇ－１ｉｍ后ｔ１／２β为７．１和４．１ｈ，ＡＵＣ与剂量呈正比，ＣＬＳ相近，生物利用度为０．６２．体外［１２５Ｉ］ｖＮＧＦ与血清最大结合率２４．６％±０．４％，平衡解离常数３．２±０．３ｎｍｏｌ·Ｌ－１．ｉｍ后颈上神经节，注药侧和对侧坐骨神经放射性明显高于血清，注药侧最高，不被１００倍非标ｖＮＧＦ抑制．主要经尿排泄，２ｄ排出约８６％．     

基因重组人白细胞介素—2在小鼠的药物动力学和分布

Ｉｎｄｏｇｅｎ法制备１２５Ｉ－ｒＩＬ－２，放射纯度９５％。ｉｖ后快速，慢速分布和消除Ｔ１／２分别为＜２，３０－１２０和６－１５ｈ，ＡＵＣ与剂量呈正比。血尿原药占８１±１３％。ｉｍ生物利用度０。５７。ｉｖ后ｍｉｎ浓度顺序为肝＞胆汁＞肾＞血＞肾上腺＞血浆＞肺＞甲状腺＞脾＞小肠＞肠系膜淋巴结＞肠内容＞卵巢＞心＞膀胱＞胸腺＞粪＞肌肉＞睾丸＞脑＞脂肪。２４ｈ排出８０％第２天５％。     

氚标记盐酸川丁特罗的合成和大鼠口服后排泄动力学（英文）

目的探讨大鼠口服放射性氚标记盐酸川丁特罗([3H]SPFF)后经尿、粪和胆汁的排泄动力学特征。方法采用化学法合成[3H]SPFF,并进行放化纯度鉴定。粪尿排泄实验观察SD大鼠经口45.5 MBq·kg-1(1 mg·kg-1)给药后168 h内经尿和粪累积放射性排出率。胆汁排泄实验观察胆汁引流模型大鼠给药后,72 h内胆汁累积放射性排出率。HPLC-放射性检测法鉴定单只大鼠尿和胆汁中放射性成分组成。结果化学法合成获得5 m L[3H]SPFF甲醇溶液(比活度403 GBq·g-1),化学纯度>96%,放化纯>97%。粪尿排泄实验的结果表明,经口给药后,SD大鼠体内放射性物质经泌尿系统排出较快,168 h经尿粪累积排出率达84.74%,其中尿回收56.63%,粪回收28.10%。胆汁排泄实验显示,给药后3 d,经胆汁放射性累积排出率为29.3%。放射性组成分析结果显示,单只SD大鼠给药后72 h尿液中累积总放射性排出量占给药量的48.61%,其中原型占4.71%,产物占42.62%。72 h胆汁中累积总放射性排出量占给药量的28.14%,其中原型占9.51%,产物占18.63%。结论大鼠经口盐酸川丁特罗后吸收完全,主要经尿液以代谢物形式排泄。     

利福喷丁的临床药物动力学研究

本文报道利福喷丁正常人药物动力学研究结果，健康志愿者１０人单剂口服利福喷丁粉剂及胶囊６００ｍｇ后的体内过程均符合血管外一室模型，其血药峰浓度分别为１７．４３ｍｇ／Ｌ（粉剂）和１８．３８ｍｇ／Ｌ（胶囊），达峰时间为９，７０ｈ（粉剂和）和８．２１ｈ（胶囊），消除半衰期（ｔ１／２ｋｅ）为１９．９０ｈ（粉剂）和１９．４２ｈ（胶囊），以上各项参数经统计学处理均无明显意义，胶囊的相对生物利用度为１０４．７２％，口服该药后有少量自尿中以原形排出体外，给药后２ｈ内分别排出给药量的１１．３０％（粉剂）和１１，２９％（胶囊）。     

重组葡激酶溶栓作用的实验研究

目的　研究重组葡激酶对体内外血栓的溶解作用。方法　采用体外纤维蛋白溶解法,家兔体内纤维蛋白溶解试验,胶原蛋白 肾上腺素诱发小鼠体内脑血栓形成模型及静脉结扎形成大鼠下腔静脉血栓模型。结果　重组葡激酶体外给药对纤维蛋白具有显著溶解作用,使家兔血浆优球蛋白溶解时间明显缩短,给药后０－５至２ｈ间血浆鱼精蛋白试验均呈阳性反应,但对血浆纤维蛋白原含量无显著影响;可显著降低脑血栓小鼠死亡率,缩短偏瘫动物的恢复时间;对结扎形成的大鼠下腔静脉血栓湿重有明显降低,给药后血栓所占血管面积明显减少。结论　重组葡激酶具有极显著溶解体内外血栓的作用,等剂量条件下,作用优于尿激酶。     

新抗肿瘤化合物8-氯腺苷在大鼠体内的药代动力学研究

目的：探讨一次静注８－氯腺苷在大鼠体内药代动力学的规律及特点,为临床实验提供理论依据。方法：给大鼠单次静注４种剂量８－氯腺苷后,应用ＨＰＬＣ测定在体液和组织中原形物８－氯腺苷的含量。结果：８－氯腺苷在大鼠体内迅速转化为代谢产物,其清除半衰期为１ｈ左右,除脂肪,脑,睾丸组织外,８－氯腺苷在体内分布广泛,药物血浆蛋白结合率在１０～４０μｇ／ｍｌ浓度范围为３７％,主要以代谢物形成从尿及胆汁中排泄,结论,     

盐酸加替沙星的药代动力学研究

目的：研究狗和大鼠口服盐酸加替沙星的吸收、分布和排泄。为临床合理用药提供依据。方法：狗口服盐酸加替沙星５，１０和２０ｍｇ／ｋｇ后０．２５，０．５，０．７５，１，２，４，８，１２和２４ｈ分别从前肢胫前静脉取血，用微生物法测定血药浓度并计算药代动力学参数。大鼠口服２０ｍｇ／ｋｇ盐酸加替沙星后５，１５ｍｉｎ和４ｈ测定各组织的药物浓度；对５只大鼠进行胆管插管，另５只置于代谢笼中，口服盐酸加替沙星２０ｍｇ／ｋｇ，４８ｈ内分别收集胆汁和尿，测定药物累积排除率；用透析法测定物药的狗血浆蛋白结合率。结果：该药药代动力学过程符合一室模型，５，１０和２０ｍｇ／ｋｇ剂量组峰浓度（Ｃｍａｘ）分别为２．０１，３．１８和８．６７μｇ／ｍｌ，与血药浓度呈线性关系，达峰时间（Ｔｍａｘ）分别为１．２７，１．７８和１．６３ｈ，吸收半衰期（ｔ１／２     

国产阿洛西林人体药动学,生物利用度研究

８名健康男性志愿者单剂静注和肌注１ｇ国产阿洛西林后的药物动力学、生物利用度的研究及阿洛西林对β－内酰胺酶的稳定性的测定结果显示：静注和肌注后药物在体内的转运过程符合二室开放模型。静注后即刻血药浓度为２１９．８４μｇ／ｍｌ。肌注后５ｍｉｎ血药浓度为１０．７９μｇ／ｍｌ，约３０ｍｉｎ达峰，峰浓度为４３．２４μｇ／ｍｌ。静注和肌注后分布相半衰期分别为０．１７和０．２９ｈ，消除相半衰期为１．６０和１．８４ｈ，药—时曲线下面积为１１５．９７和７１．８８μｇｈ／ｍｌ，生物利用度为６１．９８％。２４ｈ尿排泄率为７０．３１％和６８．５６％。本品对质粒和染色体介导的β－内酰胺酶均不稳定。     

硫酸奈替米星在大鼠体内的药代动力学

目的研究硫酸奈替米星在大鼠体内分布和排泄情况。方法大鼠ｉｖ给药后，采用高效液相色谱－间接光度检测（ＨＰＬＣ－ＩＰＤ）法测定组织和体液中药物浓度，并计算药动学参数。结果血药浓度－时间曲线符合一室开放模型，不同给药剂量时其体内Ｔ１／２为３．０１～３．６２ｈ；组织中药物浓度以肝、脾、肺、肾中最高，脂肪和脑中较低；平均血浆蛋白结合率为６．８％～１７．４％；尿、粪和胆汁２４ｈ排泄原型药物量占给药量的７４．７％，１．７０％和４．８４％。结论硫酸奈替米星在大鼠体内组织分布具有选择性，蛋白结合率低，主要经肾脏以原型排泄。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.